A growing body of evidence indicates that the risk of acquiring malaria and morbidity is determined by host genetic factors and the genotype of the infecting parasite strain. The major goal of this study is to better understand the impact that polymorphisms in RBC receptors, specifically glycophorin B (GPB), as well as the impact that the parasites[unreadable] repertoire of invasion ligand variants have on the variety of invasion pathways used by P. falciparum in two endemic regions of the Brazilian Amazon. The merozoites of P. falciparum invade through several pathways using different RBC receptors, which include the glycophorins (GPA, GPB and GPC), Band 3 and others whose identity has not yet been determined. RBC specificity is dependent on ligandreceptor interactions and these are not static in P. falciparum, partly to provide greater flexibility to the parasite. Field isolates may show even greater variability than do the laboratory isolates in which these pathways have been defined. The underlying hypothesis of this application is that both host and parasite genetic factors may drive the emergence of distinct RBC invasion pathways in P. falciparum endemic regions. To better understand the contribution of host and parasite factors involved in this process, we will study the highly admixed Brazilian Amazon population and the parasites to which they are exposed. Our initial studies have shown that the GPB S variant is more frequent in individuals who have P. falciparum infection in two endemic regions in Brazil. Moreover, we found that the Amazonian isolates have limited repertoire of invasion ligands when compared to laboratory strains and that they express unique variants some of which are associated with a defined invasion profile of the corresponding field isolates. To better understand RBC invasion by P. falciparum in the field and determine whether the molecular interactions between parasite ligands and RBC receptors observed in laboratory isolates are relevant to malaria infection in the field the following aims are proposed: 1) To establish whether molecular variation in the GYPB gene, particularly the one that generates the GYPB*S/s alleles, influences host susceptibility to infection with P. falciparum in two distinct Brazilian Amazon endemic regions. The allelic and haplotypic frequencies of the various GYPB variants will be compared between ethnically matched case and control groups within each endemic site, and between sites. 2) To determine the impact of defined GYPB polymorphisms on RBC invasion by a subgroup of Brazilian Amazon field isolates that predominantly uses the GPB invasion pathway. 3) To study the association between P. falciparum ligand polymorphisms and the RBC invasion profiles used by the Amazonian field isolates and/or the ability of the variant ligand to bind to RBCs with defined phenotypes. Our studies will likely generate a greater focus on GPB as an important RBC receptor for field isolates invasion, and motivate the search for the GPB parasite ligand which could then become also an important vaccine candidate. Our studies could also impact development of global vaccines against P. falciparum malaria that target multiple determinants of merozoite invasion.